Large-scale association analyses identify host factors influencing human gut microbiome composition

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected...

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Vydáno v:Nature genetics Ročník 53; číslo 2; s. 156 - 165
Hlavní autoři: Kurilshikov, Alexander, Medina-Gomez, Carolina, Bacigalupe, Rodrigo, Radjabzadeh, Djawad, Wang, Jun, Demirkan, Ayse, Le Roy, Caroline I., Raygoza Garay, Juan Antonio, Finnicum, Casey T., Liu, Xingrong, Zhernakova, Daria V., Bonder, Marc Jan, Hansen, Tue H., Frost, Fabian, Rühlemann, Malte C., Turpin, Williams, Moon, Jee-Young, Kim, Han-Na, Lüll, Kreete, Barkan, Elad, Shah, Shiraz A., Fornage, Myriam, Szopinska-Tokov, Joanna, Wallen, Zachary D., Borisevich, Dmitrii, Agreus, Lars, Andreasson, Anna, Bang, Corinna, Bedrani, Larbi, Bell, Jordana T., Bisgaard, Hans, Boehnke, Michael, Boomsma, Dorret I., Burk, Robert D., Claringbould, Annique, Croitoru, Kenneth, Davies, Gareth E., van Duijn, Cornelia M., Duijts, Liesbeth, Falony, Gwen, Fu, Jingyuan, van der Graaf, Adriaan, Hansen, Torben, Homuth, Georg, Hughes, David A., Ijzerman, Richard G., Jackson, Matthew A., Jaddoe, Vincent W. V., Joossens, Marie, Jørgensen, Torben, Keszthelyi, Daniel, Knight, Rob, Laakso, Markku, Laudes, Matthias, Launer, Lenore J., Lieb, Wolfgang, Lusis, Aldons J., Masclee, Ad A. M., Moll, Henriette A., Mujagic, Zlatan, Qibin, Qi, Rothschild, Daphna, Shin, Hocheol, Sørensen, Søren J., Steves, Claire J., Thorsen, Jonathan, Timpson, Nicholas J., Vieira-Silva, Sara, Völker, Uwe, Völzke, Henry, Võsa, Urmo, Wade, Kaitlin H., Walter, Susanna, Watanabe, Kyoko, Weiss, Stefan, Weiss, Frank U., Weissbrod, Omer, Westra, Harm-Jan, Willemsen, Gonneke, Payami, Haydeh, Jonkers, Daisy M. A. E., Arias Vasquez, Alejandro, de Geus, Eco J. C., Stokholm, Jakob, Segal, Eran, Kim, Hyung-Lae, Kaplan, Robert C., Spector, Tim D., Uitterlinden, Andre G., Rivadeneira, Fernando, Franke, Andre, Lerch, Markus M., Franke, Lude, Sanna, Serena, D’Amato, Mauro, Pedersen, Oluf, Paterson, Andrew D., Kraaij, Robert, Raes, Jeroen, Zhernakova, Alexandra
Médium: Journal Article
Jazyk:angličtina
Vydáno: New York Nature Publishing Group US 01.02.2021
Nature Publishing Group
Témata:
45/47
45/61
631/208/205/2138
631/326
Adolescent
Adult
Agriculture
Animal Genetics and Genomics
Bifidobacterium - genetics
Biomedical and Life Sciences
Biomedicine
Cancer Research
Child
Child, Preschool
Cohort Studies
Female
Gastrointestinal Microbiome - genetics
Gastrointestinal Microbiome - physiology
Gene Function
Genetic aspects
Genetic Variation
Genome-Wide Association Study
Host-bacteria relationships
Human Genetics
Humans
Lactase - genetics
Linkage Disequilibrium
Male
Mendelian Randomization Analysis
Metabolism - genetics
Microbiota (Symbiotic organisms)
Physiological aspects
Quantitative Trait Loci
RNA, Ribosomal, 16S
Netherlands
ISSN:1061-4036, 1546-1718, 1546-1718
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Popis
Shrnutí:To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant ( P  < 5 × 10 −8 ) threshold. One locus, the lactase ( LCT ) gene locus, reached study-wide significance (genome-wide association study signal: P  = 1.28 × 10 −20 ), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10 −10  <  P  < 5 × 10 −8 ) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis. Analysis of human genotypes and 16S microbiome data of 18,473 individuals from 25 cohorts through a genome-wide association study, a phenome-wide association study and Mendelian randomization identifies host genetic and microbial trait associations.
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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denotes shared last authorship
denotes shared first authorship
A.K, A.Z., R.Kr, C.M.G., L.F. and J.R. conceived and designed the study. A.K., C.M.G., R.B., D.R. and J.W. were responsible for coordinating and performing meta-analysis. A.D., C.L.R., J.A.R.G., C.T.F., X.L., D.Z., M.J.B. lead the specific downstream analyses, and should be considered as shared second authors. Specifically, A.D. performed the PheWAS analysis, C.L.R. and C.T. F. performed the heritability analysis in TwinsUK and NTR cohorts, respectively, and J.A.R.G performed the age-related analysis of LCT locus. X.L. ran and interpreted the FUMA analysis, D.Z. ran and interpreted the mendelian randomization analysis. M.J.B. substantially contributed to the development of the analysis pipeline and protocols. RK, JR and AZ jointly supervised the project. A. vd G., A.C., H.J.W., Ur.V., M.J.B., S.S. and L.F. developed the pipeline for the meta-analysis and contributed to the methodology and statistical analysis. K.W. contributed to the PheWAS enrichment analysis. A.K., C.M.G., R.B., D.R., J.W., A.D., C.L.R., J.A.R.G., C.T.F., X.L., D.Z., M.J.B., M.D.A., S.S., R.Kr., J.R. and A.Z. wrote the manuscript, with contributions from all authors.
K.A.M, L.J.L and M.F collected and managed the CARDIA cohort. A.D.P, J.A.R.G., K.C., L.B. and W.T. collected and managed the GEM cohort. H.B., J.S., J.T., S.A.S, and S.J.S collected and managed the COPSAC study. D.B., O.P., T.H., T.J., and T.H.H. collected and managed the DanFunD study. D.A.H., G.F., J.R., J.W., K.H.W., M.J., N.J.T., R.Y.T., R.B. and S.V.S. collected, genotyped and managed the FGFP study. C.M.G, F.R., H.A.M., L.D. and V.W.V.J. collected and managed the Generation R study. H.N.K., H.S. and H.L.K. collected and managed the KSCS study. C.W., J.F., A.Z., L.F., S.S. and A.K. collected and managed the LLD cohort. A.J.L., E.O., K.L., M.Lk. and M.B. collected and managed the METSIM cohort. A.A.M.M., D.M.A.E.J., D.K. and Z.M. collected and managed the MIBS-CO cohort. H.P. and ZDW collected and managed the NGRC cohort. C.T.F., D.I.B., E.J.C.G., G.E.D., G.W. and R.G.I collected and managed the NTR cohort. Da.R., E.B., E.S. and O.W. collected and managed the PNP cohort. A.A., L.A., M.D.A., Su.W. and X.L. collected and managed the PopCol cohort. A.F., C.B., M.C.R., M.Ld and W.L collected and managed the BSPSPC and FOCUS cohorts. A.G.U., C.Mv.D, Dj.R. and R.Kr. collected and managed the RS cohort. F.F., F.U.W., G.H., H.V., M.M.L, St. W. and Uw.V. collected and managed the SHIP and TREND cohorts. L.Y.M., Q.Q., R.Kn., R.C.K. and R.D.B collected and managed the SOL cohort. C.I.L.R, C.J.S., J.T.B., M.A.J. and T.D.S. collected and managed the TwinsUK cohort. A.A.V. and J.S.T contributed to the discussion. All authors approved the final manuscript.
Author contributions
ISSN:1061-4036
1546-1718
1546-1718
DOI:10.1038/s41588-020-00763-1